The present invention is related to stabilized povidone-iodine solutions and a novel method of preparing the same. The present invention is further related to microbicidal ophthalmic preparations comprising povidone-iodine.
Povidone-iodine (polyvinylpyrrolidine-iodine or PVP-I) U.S.P. (U.S. Pharmacopeia) is the raw material used in the preparation of all PVP-I containing formulations.
Provione-iodine is a complex of iodine with povidone. It contains not less than 9.0% by weight, and not more than 12% by weight of available-iodine (titratable iodine) calculated on a dry basis. Povidone Iodine USP has a specification for iodide ion of not more than 6.6% by weight on a dry basis.
PVP-I solutions, as well as other iodophor solutions, have been packaged for medicinal use, e.g. in soft plastic bottles or containers, which can be used for various medicinal purposes, e.g. douching. However, a severe problem that has been encountered with such packaged iodophor solutions, is that elemental iodine (equilibrium iodine) has leached through the packaging itself. In the past, this resulted both in a decrease in stability and medicinal capacity of the iodophor solution contained within the packaging, and made it difficult to handle such packaging since the elemental iodine which leached therethrough caused staining and burning if touched.
The problems associated with packaging such PVP-I solutions in soft plastic bottles o containers have been overcome through the addition of other stabilizers or iodine donating species such as iodate salts, as disclosed in U.S. Pat. No. 4,113,857 (Shetty), and the use of iodide salts, as disclosed in U.S. Pat. No. 4,996,048 (Bhagwat et al.)
In Bhagwat et al., for example, the iodophor solution itself preferably comprises about 0.01-0.03% of iodide therein, in addition to the additional amount of iodide that has been introduced which improves the stability of the iodophor and minimizes leaching of iodine through the packaging. As disclosed therein, at least about 0.01% by weight of the additional iodide, based on the iodophor solution, and up to about 4.0% of the additional iodide is introduced into the packaging. The additional iodide is preferably KI.
Although PVP-I solutions are known to exert microbicidal activity, stabilizing PVP-I solutions for ophthalmic use was problematic prior to the present invention, and in view of the stability problems associated with dilute PVP-I solutions, it has not been possible to date to provide an acceptable formulation of dilute PVP-I solutions, such as for ophthalmic use. For example, the introduction of donating species such as iodate into a PVP-I solution is not considered to be desirable when the solution is to be used as an ophthalmic preparation because iodate (and probably iodide) are known to be irritating and toxic to the pigment epithelium of the retina. Thus, a PVP-I solution stabilized via the addition of, for example, potassium iodide and/or potassium iodate would not be useful as an ophthalmic preparation.
It is generally recognized that an ophthalmic solution should have the same pH as human lacrimal fluid. Such a result can be obtained for an ophthalmic preparation via the use of a buffer system approaching physiological pH. It is common practice to control the pH of solutions through the use of buffers, which are pairs of related chemical compounds capable of resisting large changes in the pH of a solution caused by the addition of small amounts of acid or base, regardless of the source. For example, borate buffers (which comprise weak acids and their conjugate bases) have been used in ophthalmic preparations.
Historically, PVP-I solutions have been buffered to at least a pH of 5. This prior art is a known requirement for physiological compatibility and stability of aqueous PVP-I solutions. It has also long been recognized in the art that the more dilute the PVP-I solution, the less stable it is.
It has been found that for dilute concentrations of PVP-I which are microbicidal, especially those concentrations of PVP-I which would be useful in ophthalmic preparations, the use of buffers do not stabilize the solution. For example, if a 0.3% PVP-I solution buffered at a pH of 5.4 is prepared without the use of stabilizers or iodine donating species, the stability of such solutions in glass bottles cannot be maintained.
It is therefore an object of the present invention to provide a novel stabilized solution of an iodophor, most particularly PVP-I, which can be stored in nonpermeable containers, such as glass bottles.
It is another object of the present invention to provide a novel stabilized microbicidal solution of PVP-I which can be stored in glass bottles and which is useful as an ophthalmic preparation.
It is a further object of the present invention to provide a novel stabilized microbicidal ophthalmic preparation containing a dilute solution of PVP-I which can be stored in glass bottles and which is not irritating or toxic to the eye.
It is a further object of the present invention to provide a method of using a PVP-I solution as an anti-microbial for ophthalmic use.
It is a further object of the present invention to provide a process for preparing a dilute PVP-I solution which is effective as a microbicidal for ophthalmic use and which is stable when stored in glass bottles.
It is a further object of the present invention to provide a method of treating the eye via the use of a microbicidal stabilized ophthalmic solution comprising PVP-I.